Sulfonic ester analogues of nitrogen mustards



Patented Mar. 2, 1954 ?ia EENi'E' S-IEFEFBNIQ 'ESEERJ ANALOGUES F NIEBRIMSEN MUSTARDS James M'.-;sra ue,,,mexe1 mu, anutsa'wavae-Ln Eligelliandt'g'Cbllixigdale, 2a., 1st"Cityplziim, azicorppration of assignors to Merck "New Jersey Noflhiaming: AnplicationMayl, 1951,

. Serial No. 22 3072? 1;; Thislinuentioni relates; tamew-z sulfonio; ester; analdgsl'oijnitrogen mustards,.andvmoreiparticuw larmtolcompounds hai ing theiollowing lineralt strnaturaLiormula:v

In this compound R is-selectedifromralkykradie-- calsehavingi up {130 i canbomatoms aralkylr radicarlahaving; un te-:10 carbon atoms; cycleall zyilv radicals? selected-.- frame cyclopentylw andt. CXgIOv-w hexyl.iandsatheeradicalr:GH2-H2X1 Thec-alksgl; radical= canzbe aaz straighter :branchedcchai-nsandw cam; includes a terminals; saturated ring. The; radicaLR car-11 also includaifor example. alkoxm groups, halogen cggoupsr-nether rlinkagesstataleastri twozcarbonsvremoved .fromztheinitmggene Racannot'ibeihydrogem.

Irrrthesknowna COmpQUndSrDfJthiSxbXHShX? is as halogenssucm, asa-ohlorinen Representatitzemqm+- pounds, whemX ;isr-as'ha1QgQn:-and;Riszasgabouee set:fnnth;iare-illustrated.imthaarticle,':Ghemica]i= Reactions-mic the wNitnogenr Mnstand Gasesizfin eight sections: byeMax; Bergmann iandrtothera; inr, the nseptemberr 194% issue f? :IheJounnahof: Ora ganicichemistry; cvoln 11;; Numherefi, pagesrfil Satay 591*inclusi-ver- Vt herhthe. -free:base:isidissolyedginta pplale Solis vent ,thercompoundeundergpescaniinternahcychzatinnit'erform the follawingflons The mate i of 'cyclization ...iS ,thesrat'e. dtermitiing: step ofithe.oizeralllreactitm.w To .dterminectfie; relative ratesoiiformationfloiithe cyolizedifi on,

thereioilajt is.v merely;necessary toladctftheicom= pound-' to a solution containing "sodium 'thiosul fate and. to-measure=the ratepfdecrease of the sodihm'thiosulfate. concentrati-onr For example; tests' shbwthat 1 to =react one moleof 2;2--di chldro N -methyl diethylamine with 1.8 mole of thiosulfate, more than 35 minutesisrequired;

In the case of the known compounds in which x' is'whalegen such as =-ch1o'r-ine; the=rate of this OYGHZ'QMUHHS therefore quite slowz' In: accord ance with! the present invention; it' 'has been dis covered that if the X radieal f thecompound is a sulfonic ester radical, the rateofcyclization is very unexpectedly increased, and in most. instances is too rapid td-bemeasured readily'at" room temperature.

This rapidrate'of cyclizatio'n of the compounds ofrt'he inyention is of particularimportance when the material is used as atherapeutic agent. The compounds of the invention exhibit viricidal acti-vity' and i some of" them show radibmim'e-tic" activity.

The reasonfortheextremely rapid cycli'zation ofthecompound's of {the 'inventioniisnot under stood. It-"would'beexpected th'atsuchja marked; diiference as ismb'servedwould not -'occur-'m'erely by the substitution for the halogen radical "ofia"- sulfoni'cj-acid "estenradioal."

The: compounds of "the invention;- that is; those imwhich X 'is'ay-sulfo'nic acid ester, may*-t1"1ere'-- f'tire be" represented by'theformular om--cm-osoan*-R* The R). Subfsti'tjuentmay be any lower al'kyYradi cal up to eight carbon, atoms, anditjmay be either. straight ioipbra'nchedi chain" 0r R mayvbelaryl on'aralkyl'i such as jpheny1"p. --to1y1 or .henzy lj.v or; arylofxyalk'yl suchas phenoxyethylh Representa, tives jof', these .organic,.radicalsi will be. apparent fiom the subsequentexamplesh. V

Theisu'hstitiient Rjof. the compounds of the in.- ventibn ,may be, s elected. from the class ,d ef nedli aloove,,,a nd more. specifically illustrated in t the,

a aforementibnedartiole .ibywBfergmann andj'othersi The exact. character. c ofjRl is, not critical? innthe: present. linventi'on within (this: class. ofiradibals}. iriasmuchas the,inventiontisiprimarily,concerned; withith'eisulioniciacidlester character. ofsth'e'sublstitnentX. Itlmay becbservedthat an,ethy1ene.

radicaljfis;present,bet eennthevester oxygenand; nitrogensconstitiients. oi the comppundfl Either". OfJthese two-carbons may bearninsteadbf hydrios gen atoms.substituents such; aszltiwer. alkyl radii-v; cals without materially; impairing the desired;

cyclization or the intended results of the invention.

To obtain the compounds of the invention it is possible to follow several different procedures. For example, the hydro-chloride of a 2,2'-dichloro-N-substituted diethylamine may be treated with the silver salt of the selected sulfonic acid according to the following scheme:

CHiCHrCLHCl In practice the reactants are dissolved in a polar non-hydroxylic solvent such as a lower alkyl cyanide, for example, methyl cyanide. The mixture should be heated for a period from 3 to 6 hours at a. temperature of from 60 to 100 C. At the end of this time the mixture is cooled and the precipitated silver chloride separated. The sulfonic acid ester of the 2-dialkylaminoethanol is recovered in the form of its sulfonic acid salt by evaporating the solvent.

Another method by which the products of the invention may be obtained is by treating the 2,2- dihydroxy-N-substituted diethylamine with the anhydride of the selected sulfohic acid, as illustrated by the following:

In carrying out this reaction the ingredients may be mixed together in the presence of a solvent such as benzene, chloroform, or ether and the mixture allowed to stand at room temperature for a period of 3 to hours, or the solution may be heated to refluxing for an hour. The desired sulfonic acid ester is obtained in the form of its sulfonic acid salt by evaporating the solvent.

Somewhat higher yields are obtained if the 2,2- dihydroxy-N-substituted-diethylamine is treated with the alkanesulfonic anhydride in the presence of a lower alkyl cyanide such as methyl cyanide as a solvent. This reaction may be carried out at reflux temperature for 1 to 7 hours. To recover the desired product, the isolation procedure mentioned above may be carried out.

' The invention will be further illustrated by reference to the following examples:

Example 1.-2,2'-dihydroxy-N-methyldiethylamine, 7.27 g. (0.0610 mole) was dissolved in ml. of dry acetonitrile. The solution was added dropwise to a solution of 23.28 g. (0.134 mole) of methanesulfonic anhydride in 65 ml. of dry acetonitrile while stirring and maintaining the reaction mixture at room temperature. The solution was allowed to stand overnight at room temperature and the solvent then evaporated at 55-60 under reduced pressure. The syrup residue was dissolved in 68 ml. of a 4.43 N solution of dry hydrogen chloride in absolute alcohol, the solution diluted with 150 m1. of absolute ether and chilled. The crystalline product that separated was recrystallized from a mixture of methanol containing 1% of water and ether. The yield of white crystalline product, 2,2'-di-mesyloxy-N-methyldiethylamine hydrochloride, M. P. 112-113 was 13.47 g. (57%).

Example 2.--2,2',2",trihydroxytriethylamine, 2.73 g. (0.0183 mole) dissolved in 10 ml. of dry acetonitrile was added dropwise to a solution of 11.0 g. (0.063 mole) of methanesulfonic anhydride in 25 ml. of dry acetonitrile while maintaining the reaction mixture at room temperature. After standing overnight at room temperature, the mixture was heated to refluxing for 1 hour. The solvent then was evaporated and the residue dried at50-55 C. under reduced pressure. The viscous syrupy residue weighed 13.80 g. and contained 56% of the methanesulfonic acid salt of 2,2,2"-trimesy1oxytriethylamine as estimated by titration against sodium thiosulfate. This corresponds to a yield of 88% of the theoretical.

Example 3.-2,2'-dich1oro-N-cyclohexyldiethylamine hydrochloride, 2.61 g. (0.01 mole), dissolved in ml. of hot acetonitrile was added dropwise to a solution of 8.37 g. (0.03 mole) of silver p-toluenesulfonate in 30 ml. of dry acetonitrile. The reaction mixture was refluxed with stirring for 6 hours. The precipitated silver chloride then was removed by filtration and the solvent evaporated at 40-50 under reduced pressure. The residue contained 79% of the p-toluenesulfonic acid salt of 2,2'-di-(p-tosyloxy)-N- cyclohexyldiethylamine as estimated by titration against sodium thiosulfate.

Example 4.-By substituting 6.09 g. (0.03 mole) of silver methanesulfonate for the silver p-toluenesulfonate of Example 3 and following the procedure of Example 3, except that the reaction mixture was refluxed for only 3 hours, a viscous yellow syrup containing 79% of the methanesulfonic acid salt of 2,2-di-(mesyloxy) -N-cyclohexyldiethylamine was obtained.

Example 5.The process of Example 4 was carried out but using an equimolecular amount of 2,2-dichloro-N-butyldiethylamine hydrochloride instead of the corresponding cyclohexyl compound. The methanesulfonic acid salt of 2,2- di-mesyloxy-N-butyldiethylamine was obtained.

Example 6.-The process of Example 4 was carried out but using an equimolecular amount of 2,2'-dich1oro-N-octyldiethylamine hydrochloride instead of the corresponding cyclohexyl compound. The methanesulfonic acid salt of 2,2- di-mesyloxy-N-octyldiethylamine was obtained.

Example 7.-2 ,2 -dihydroxy-N- c-naphthyl) diethylamine, 2.31 g. (0.01 mole) was dissolved in 60 ml. of dry acetonitrile. The solution was added dropwise with stirring to a warm solution of 6.53 g. (0.02 mole) of p-toluenesulfonic anhydride in 60 ml. of dry acetonitrile. The yelloworange reaction mixture was refluxed for 6% hours after the addition was complete, then allowed to stand overnight at room temperature. The solvent was evaporated and the residue dried to constant weight at 50-55 C. under reduced pressure. The residue then was dissolved in absolute acetone, the solution filtered, diluted with absolut ethanol and chilled. The crystalline product that separated was recrystallized from a mixture of absolute acetone and absolute ethanol to give 1.53 g. (28%) of 2,2'-di-(p-tosyloxy) N-(p-naphthyl) -diethylamine, M. P. 113-114 C.

Example 8.-The process of Example 3 was carried out but using an equimolecular amount of silver benzenesulfonate instead of the silver p-toluenesulfonate. The compound obtained was the benzenesulfonic acid salt of 2,2'-di-benzenesulfonyloxy-N-cyclohexyldiethylamine.

Example 9.-The process of Example 3 was carried out but using an equimolecular amount of silver a-toluenesulfonate instead of the silver p-toluenesulfonate. The compound obtained was the a-toluenesulfonic acid salt of 2,2'-di-(atosyloxy) -N- cyclohexyldiethylamine.

It has been pointed out above that tests show that to react 1 mole of 2,2'-dichloro-N-methyldiethylamine with 1.8 mole of thiosulfate, more than 35 minutes is required at 25 C. The rapidity of the cyclization which occurs with compounds of the invention is shown by the fact that 2,2'-dimesyloxy-N-methyl-diethylamine reacts with 1.8 mole of thiosulfate in less than 5 minutes at 25 C.

Other examples of the invention will be apparent from a consideration of the compounds represented to be therapeutically effective in the above mentioned article by Bergmann and others, using those compounds as starting materials and carrying out the reactions of the above examples.

It will be noted that the product obtained from carrying out the reactions set forth above, is the salt of the same sulfonic acid which is involved It will be appreciated from acid ester structure of the compound and that the acid that forms the salt of the compound is relatively unimportant. Thus, although the compounds obtained in the above examples have as the salt-forming acid the same acid that occurs in the ester, the invention contemplates salts of other acids such as the hydrochloric, sulfuric, and other sulfonic acids, as well as carboxylic acids. The free base can be prepared from this salt by neutralization with one equivalent of an alkali, but in most instances this free base is not stable.

What is claimed is:

1. Compounds having the formula:

in which R is selected from the group consisting of alkyl radicals having up to carbon atoms,

aralkyl radicals having up to 10 carbon atoms,

cyclopentyl, cyclohexyl, CH2CH2 halogen, and CH2CH2OSO2R' radicals, and in which R is selected from the class consisting of lower alkyl radicals.

3. Compounds having the formula:

in which R is selected from the group consisting in which R is selected from the group consisting of alkyl radicals having up to 10 carbon atoms, aralkyl radicals having up to 10 carbon atoms, cyclopentyl, cyclohexyl, CH2CH2 halogen, and CH2CH20SO2R' radicals, and in which R is benzyl.

5. Compounds having the formula:

in which R is selected from the group consisting of alkyl radicals having up to 10 carbon atoms, aralkyl radicals having up to 10 carbon atoms, cyclopentyl, cyclohexyl, CH2CH2 halogen, and CH2CH2OSO2R' radicals, and in which R is tolyl.

References Cited in the file of this patent Bergmann, Journal of Organic Chemistry, vol. 11, p. 518 (1946). 

1. COMPOUNDS HAVING THE FORMULA: 